The present invention relates to granules for oral administration, containing angiotensin-converting enzyme inhibiting peptides, process for producing the granules, and tablets manufactured from the granules obtained above. The angiotensin-converting enzyme inhibiting peptides are obtained from whey separated from fermentation liquids of lactic acid bacteria or lactic acid bacteria and yeast. The granules and tablets can be used for anti-high blood pressure agent or foods, when the whey is further treated for purification, and then for granulation, and for tableting, if necessary.
The angiotensin-converting enzyme, hereinafter referred to as ACE, is mainly present in lungs and vascular endothelial cells, and acts on angiotensin I (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu) to remove a di-peptide (His-Leu) at its c-terminal and to form angiotensin II, which has a strong blood pressure increasing activity. The ACE also has an ability to decompose and to inactivate bradykinin, which decreases blood pressure. Thus, the ACE acts to increase blood pressure by producing angiotensin II on the one hand, while decomposing bradykinin to increase blood pressure. Accordingly, when the angiotensin-converting enzyme is inhibited, high blood pressure could decrease, and many drugs which contain the angiotensin-converting enzyme inhibitor have been developed and used for anti-high blood pressure.
Certain peptides were recently found to be useful, being low in toxicity and highly safe anti-high blood pressure agents, and natural and synthetic peptides are reported to be probable anti-high blood pressure drugs (Japanese Patent Publication No. 120,225/1991). It is also known that peptides containing Ile-Pro-Pro (hereinafter referred to as IPP) or Val-Pro-Pro (hereinafter referred to as VPP) as its basic peptide structure have ACE inhibiting properties, and that these peptides can be produced in large amounts by culturing certain lactic acid bacteria, or lactic acid bacteria and yeast (Japanese Patents Nos.2,782,142 and 2,782,153). Drugs or foods consisting of the peptides are proposed to be highly safe and useful in a small amount for decreasing high blood pressure in forms of oral administration, when the cultured liquid is treated for purification and separation.
It may be possible to use the fermentation liquid as is obtained in accordance with the processes described in the above patents for the ACE-inhibiting drugs or foods containing the ACE-inhibiting peptides (hereinafter referred to as ACEI peptides). However, these may have poor palatability for oral intake, and are not appropriate to drink without further purification processes, because they contain lactose, lactic acid and some other substances. Accordingly, it is desirable to remove substances other than the ACEI peptides from the liquid. Drugs or foods in a dry form including the peptides in more concentrated form than the liquid are more useful. Proteins and the ACEI peptides having IPP or VPP as its basic peptide structure, which are produced by culturing lactic acid bacteria or lactic acid bacteria and yeast, are partly hydrolyzed to form IPP and VPP in the cultured broths. The IPP and VPP in the peptides mainly show the ACE inhibitory activities.
The fermentation liquid is subjected to treatments for solid-liquid separation, including centrifugation, decantation, and filtration to obtain whey as a supernatant, which contains a major portion of the ACEI peptides. Acids and other impurities in the whey may be removed by subjecting the whey to one or a combination of the following treatments including electrodialysis, a treatment with ion exchange resins, hollow fiber membrane dialysis, reverse osmosis treatment, and hydrophobic column chromatography.
When the purified whey thus obtained are treated for producing solid oral dosage forms, such as granules, powder, and tablets, by means of conventional drying processes, the products generally have disadvantages, including over-absorption of moisture, lower density, and wider distribution in the particle size, as well as poor free-flowing properties. The wider particle distribution may often decrease efficiency in the following step of tableting, because of its moisture-absorption and poor free-flowing properties.
For example, when the purified solutions are spray-dried, the powder obtained is very fine, and accordingly, moisture absorbant. Its specific gravity is also very small, and particle distribution is very wide. When the purified whey is treated for producing granules by spray-drying and then fluidized bed granulator, the granules obtained have wider particle distribution containing very fine powder, the fine powder should absorb moisture easily, and accordingly, when abruptly exposed to hygroscopic environment, its free-flowing properties greatly decrease. These disadvantages greatly decrease manufacturing efficiency in the next step of tableting operations, for example, the entire environment of the tableting operation should be cooled or under vacuum. Powder which adheres on the surface of the die and punch, causes the tableting machine to stop, and uniform pressures on the surface of the tablets cannot be obtained, because the starting granules cannot smoothly be supplied to the drum with predetermined amounts. Accordingly, the tablets obtained lack uniformity in hardness and gravity. Moreover, manufacturing costs increase, because the procedures necessitate two different equipments and two different operation steps.
Granules obtained by using a spray-drying type fluidized bed granulator have rather narrow distribution in particle size, however, the process for producing the granules has disadvantages, including higher moisture-absorbing properties, and great decrease in the yields of the end product ACEI peptides.
The present invention provides granules for oral administration, containing angiotensin-converting enzyme inhibiting peptides, a process for producing the granules, and tablets manufactured from the granules, wherein the granules and tablets have properties of narrower particle distributions, lower moisture absorption, and heavier specific gravity, as well as higher free-flowing.
The granules manufactured in the present invention are highly safe, effective in ACE inhibitory activities when taken in small amounts, and have good palatability; nevertheless, the whey from which the granules are manufactured contain substances which absorb moisture even in a form of solid dosage forms, too much acids, and other substance.
The present invention also provides manufacturing processes for the granules in high yields of recovering ACEI peptides and ACE inhibitory activities.